joshi et al., ijpsr, 2018; vol. 9(10): 4089-4101. e-issn

Joshi et al., IJPSR, 2018; Vol. 9(10): 4089-4101. E-ISSN: 0975-8232; P-ISSN: 2320-5148

International Journal of Pharmaceutical Sciences and Research 4089

IJPSR (2018), Volume 9, Issue 10 (Review Article)

Received on 19 January, 2018; received in revised form, 19 April, 2018; accepted, 11 June, 2018; published 01 October, 2018

A REVIEW ON DIVERSIFIED USE OF THE KING OF SPICES: PIPER NIGRUM (BLACK

PEPPER)

Dirgha Raj Joshi * 1

, Abinash Chandra Shrestha 2

and Nisha Adhikari 3

College of Pharmacy 1, Institute of Pharmaceutical Research and Development, Wonkwang University,

460, Iksan-daero, Iksan, Jeolabuk-do 54538, Republic of Korea.

Department of Pharmacy 2, College of Pharmacy, Woosuk University, 443 Samnye-ro, Samnye-eup,

Wanju-gun, Jeollabuk-do Republic of Korea.

Department of Pharmacy 3, Crimson College of Technology, Butwal, Nepal.

ABSTRACT: Black pepper, the ‘King of spices’ (Piper nigrum L.), is

a widely used spice, known for its pungent odour. From time

immemorial, plant sources were used in traditional systems of

medicine and day-to-day common use, such as in meal preparation and

cosmetic purposes. This is due to their vast pharmacological potential

with minimum side effects. Among the various species of the

Piperaceae family, black pepper is one of the most popular due to its

principle pharmacological component, piperine. Which is an alkaloid

that has diverse pharmacological activities like antioxidant, anti-

obesity, antitumor, antipyretic, anticonvulsant, anti-thyroid, antifungal,

antibacterial, insecticidal, hepatoprotective, anti-asthmatic, larvicidal,

antihypertensive, anti-inflammatory, antidiabetic, antidiarrheal, bio-

availability enhancer, immunomodulator, antiepileptic, antifertility, GI

stimulant, lipid metabolism accelerator, anticancer, CNS stimulant,

diuretic, aphrodisiac, blood purifier and antiplatelet activities, etc. Due

to some religious value of black pepper, its being popular from ancient

time to modern generation. This review is aimed to provide a literature

review on recent advancement of chemistry, pharmacognosy,

pharmacological activities, new piperine based formulations and other

general use of Piper nigrum.

INTRODUCTION: Piper nigrum belongs to the

family Piperaceae, it is a perennial shrub native to

southern India, and has been extensively cultivated

there and in other tropical regions.

QUICK RESPONSE CODE

DOI: 10.13040/IJPSR.0975-8232.9(10).4089-01

Article can be accessed online on: www.ijpsr.com

DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.9(10).4089-01

As of 2013, Vietnam is the world’s largest

producer, as well as exporter, of pepper, producing

34% of the global P. nigrum crop. Due to its strong

pungency, it is regarded as the ‘King of spices’ and

it has valuable medicinal potency.

It is one of the world most common kitchen spices

and well known for its pungent chemical

constituent piperine (1-peperoyl piperidine, Fig. 2),

discovered in 1819 by Hans Christian, which has

diverse pharmacological activities. It is commonly

known as Kali mirch in Urdu and Hindi, Marich in

Keywords:

Piper nigrum,

Piperine, Black pepper,

Piperaceae, Anti-oxidant

Correspondence to Author:

Dirgha Raj Joshi

Research Assistant,

College of Pharmacy,

Institute of Pharmaceutical

Research and Development,

Wonkwang University, 460,

Iksan daero, Iksan, Jeolabuk do

54538, Republic of Korea.

E-mail: [email protected]



Nepali, Pippali in Sanskrit, Milagu in Tamil, and

Black Pepper, Peppercorn, Green pepper, White

pepper, Madagascar pepper in English 1, 2

. It is

widely accepted and most used in different

traditional systems of medicine, like the Unani and

Ayurvedic systems 4.

FIG. 1: HARVESTED BLACK PEPPER SEEDS (L.) AND PEPPER FRUIT (GREEN AND RIPENING PINK YELLOW)

FIG. 2: SOME OF THE IMPORTANT CHEMICAL CONSTITUENT OF P. NIGRUM

It has long been used to treat many diseases, such

as antihypertensive 9, antioxidant, antiplatelets,

antitumor, anticonvulsant, antithyroid, analgesic 6,

anti-inflammatory 20, 86

, antidiarrheal, anti-

spasmodic, antidepressants, immunomodulatory,

antibacterial, antifungal, hepatoprotective, etc. 1, 7

This has lead scientists to think more about it, as a

result there is much research going on regarding its

derivative synthesis 78

, SAR modification, and

testing its biological activities. The traditional and

modern uses (Cell, animal and human based study)

are summarized in Table 1.

Piperine amount varies from 1-2% in long pepper,

to 5 - 10% in commercial white and black peppers.

It increases the bioavailability of many nutrients

and drugs by inhibiting various metabolizing

enzymes 1. Piperine inhibits adipogenesis by

antagonizing PPARγ activity in 3T3-L1 Cells 3.

Like in high fat diet male Wistar rats; 40 mg/kg of

piperine significantly reduces body weight, levels

of plasma TC (Total Cholesterol), LDL (Low

Density Lipo-protein), VLDL (Very Low Density

Lipoprotein), and activity of HMG CoA reductase

in liver, heart, and aorta, also significantly increase

the level of plasma Lecithin Cholesterol Acyl

Transferase (LCAT), plasma and tissue lipoprotein

lipase (LPL) 5, 10

. Other summarized activities are

in Table 2.

Thus, piperine is a powerful candidate in regulating

obesity induced dyslipidemia, which signifies the

great importance of black pepper. Researchers have

isolated valuable compounds from black pepper

including various lignans derivatives, phenolics,

terpenes, chalcones, alkaloid, steroid, flavonoid,



dihydropipericide, N-trans-feruloyltryamine, piper-

amine and isobutyllocadienamide 11

. They have

also isolated, brachyamide B 12

, benzamide group 13

, (2E, 4E)-N-Eicosadienoyl pereridine 14

,

guineensine 15

, (2E,4E)-N-isobutyldecadienamide 16

, piperamide 17

, piperettine 19

, pipericide 18

and

other sarmentine, sarmentosine, piperolein B,

trichostachine, etc. More than 592 compounds have

been isolated and lignans (47), alkaloid/amide

(145), terpenes (89), neolignans (70) among them

along with 101 novel compounds 11

. Among these

14 compounds, there are biologically active and

many SAR modifications going on. The main pungency of P. nigrum is due to piperine

94 and

chavicine. Chavicine is an alkaloid with

diastereomeric geometric isomers of piperine.

TABLE 1: TRADITIONAL USE TO SCIENTIFICALLY PROVEN MODERN USE OF P. NIGRUM 1, 3,4-6, 8-9, 15-16, 19-21

Traditional Use Modern Use

Antiseptic, antispasmodic, aroma,

analgesic, anti-inflammatory,

anti-toxicant, aphrodisiac,

antipyretic, rheumatism, diabetes,

muscular ache, diuretic, flavor,

spirit, dyspepsia, increase salivary

secretion and promote digestion,

CNS stimulant, indigestion and

flatulence, throat ache, cold,

germicidal, blood purifier,

antibacterial, religious value,

cancer, pungency, kitchen curry,

cough, as carminative,

insecticide, etc

Cell Based Study Animal Based Study Human Based Study

Increase enzymatic

activity, increase lipid

per-oxidation,

antioxidant,

bioavailability enhancer,

immunomodulatory

effect, increase WBC

count and inhibit

adipogenesis

Antiepileptic, antifertility,

bioavailability enhancement,

anti-metastatic, stimulate

enzymatic activity, inhibit

mycobacterium growth,

hepatoprotective, increase

digestion by promoting bile

secretion, synergistic effect in

nimesulide, anti-amoebic

activity, antifibrotic effect,

antibacterial, antioxidant,

reduce glutathione, antifungal,

etc

Anti-asthmatic, anti-

oxidant, reduce high fat

diet induced oxidative

stress, GI stimulant, anti-

carcinogenic, lipid

metabolism acceleration,

anti-inflammatory,

cancer, etc

TABLE 2: NOTABLE ACTIVITIES OF PIPER NIGRUM (WHOLE) AND PIPERINE

Activities/

Model

Dose/ Duration/

Frequency

Result/

Conclusion

Enhance Bioavailability 60

Rat Blood level of vasicine and sparteine increased by piperine and P. nigrum, either by

promoting fast GI absorption or due to first pass metabolism in liver or both 22

Rat, Human

5 mg for 14 days

20μmol/L

Serum level of β-Carotene increased by piperine 23

To overcome vitamin deficiency piperine enhanced β-Carotene uptake 26

Curcumin: serum concentration, absorption, bioavailability increased by piperine 24

Human 2, 4, 5, 6, 7, 8h Piperine from black pepper via oral supplementation, increases plasma levels of

coenzyme Q10 25

20 mg; 7 days Bioavailability of propranolol and theophylline in healthy volunteers was enhanced

by piperine 36

Human, Mouse,

Rat

20 mg/kg Oral bioavailability of phenytoin (anti-seizure medication) was enhanced by

piperine 37

Affect Enzyme activity and Biotransformation

Mice, Rats and

Hamsters.

100 mg/Kg Piperine showed acute and subacute toxicity, by potentiating CCl4 induced

hepatotoxicity and increased activity of NADPH cytochrome reductase 27

Rat Piperine modulate P-glycoprotein ATPase activity (stimulation at low concentration

and inhibition at high concentration) 28

With direct interaction to enzyme caused impairment of cytochrome P4501A129

Guinea-pig small

intestine

piperine lowers the endogenous UDP-glucuronic acid content 30

Affect in Digestion

Human 1.5g/ meal Via intragastrical administration of black pepper significantly increase in pepsin and

parietal secretion, gastric cell exfoliation and K+

loss 31

Albino rat

(white)

20-142 mg/kg Piperine stimulate H2 receptor and promote gastric acid secretion and was

significantly antagonized by cimetidine (H₂ receptor antagonist) 32

Rat 20 mg %; 8

weeks

Piperine significantly enhanced intestinal lipase activity and the disaccharidases

sucrase and maltase in rat; administered along with fed, thus promote digestion 33

20 mg/day Significantly caused shortening of GI food transit time 34

12.5 or 25 Feeding piperine along with diet caused an increase in bile flow and decrease in bile

https://en.wikipedia.org/wiki/Piperine



mg/Kg; 4 weeks solids, also secretion of uronic acids in bile was enhanced 35

Anti-inflammatory, antioxidant, and anti-obesity effects

Rat 20 mg/kg; 10

weeks

Piperine and P. nigrum maintained superoxide dismutase, glutathione peroxidase,

catalase, glutathione-s-transferase, glutathione levels and reduced high fat diet

induced oxidative stress 38

Piperine showed anti-inflammatory activity in rats, where acute and chronic

experimental models induced by cotton pellet granuloma, rat paw edema and croton

oil-induced granuloma pouch; piperine was effective and it also acted partially

through stimulation of pituitary adrenal axis 40

Mouse 1 mg/mL Piperine inhibit cholesterol uptake and lowered blood lipids 39

10 mg/kg Nimesulide and piperine co-administration showed synergistic effects towards

analgesic and anti-inflammatory activity 41

(Human) Murine

dendritic cell

1h, 37°C Piperine inhibited JNK and ERK pathway, so proved reputed use in arthritis and

diabetes 41

3T3-L1 Cells Piperine antagonized PPARγ activity in 3T3-L1 cells, thus inhibits adipogenesis 3

Anti-carcinogenic and Anti-mutagenic effects

Mouse 0.98 mg Significantly piperine inhibited lungs metastasis-induced B16F10 melanoma cells in

mice 43

P. nigrum, oral administration increased life span of mice with tumor

(Ehrlich ascites) 44

50 mg/kg Lipid peroxidation, nucleic acid content, protein carbonyl and carcinogenesis are

significantly prevented due to preventing protein damage and suppressing cell

proliferation by piperine 45

Rat Chemical carcinogenesis was inhibited by P. nigrum through modulating

glutathione-S-transferase, Cytochrome P-450, malondialdehyde levels, and acid

soluble sulfhydryl content 46

Role in fertility and Hormonal effect

Rat 5-10 mg/kg Piperine cause marked increase in serum gonadotropin, significant decrease in

weight of testes and decrease in intra-testicular testosterone level without change in

normal serum testosterone titres 47

Infusion of piperine in rat, induced catecholamine secretion from the adrenal

medulla 48

A large variety of aromatic and volatile compounds

are present in P. nigrum and it possesses diverse

potential for cosmetic, perfumery, medicine, and

kitchen spices. Some of the categorized aromatic

and volatile principles found in it are summarized

in Table 3.

TABLE 3: AROMATIC AND VOLATILE COMPOUNDS

PRESENT IN P. NIGRUM 21, 49

Monoterpenes Sesquiterpenes Others

Sabinene

Limonene

Camphene

Myrcene

Cis-Ocimene

Terpinolene

1,8-Cineole

α-Thujene

α-Pinene

α-Phellandrene

α-Terpinolene

β-Pinene

β-Phellandrene

γ-Terpinene

δ3-Carene

Caryophyllene oxide

α-Cis-Bergamotene

α-Trans-

Bergamotene

α-Copaene

α-Cubebene

α-Selinenes

β-Bisabolene

β-Caryophyllene

β-Cubebene

β-Elmenes

γ-Cadinene

δ- Cadinene

ar-Curcumene

Cinnamic acid

Benzaldehyde

Eugenol

Methyleugenol

Myristicin

m-Methyl

acetophenone

n-Butyrophenone

Piperonic acid

Piperonal

Phenyl acetic acid

P-Methyl

acetophenone

Safrole

Trans-Anethole

The species possesses flavor, color and aroma also

provides diverse therapeutic potency. Many

writings of the Ayurveda describe the diversified

use of P. nigrum. Day-to-day, new updates in its

research for specific pharmacological action

established by experimental and clinical studies

signifies the traditional ethnomedicinal use of P.

nigrum. Many active constituents are already being

isolated from it and among them, some show

significant pharmacological potency.

Some of the notable pharmacological activity

showed by P. nigrum and its isolated constituents

that attracts our todays research are antioxidant,

antibacterial 79

, antiviral, antifungal, antimicrobial,

anti-adipogenesis, insecticidal, larvicidal, pesticide,

anti-diarrheal, analgesic and antipyretic, anti-

apoptotic, antidepressant, antimutagenic and

anticancer, immunomodulatory, antispasmodic,

anti-thyroid, cold extremities, gastric ailments,

hepatoprotective, increase pancreatic enzymes,

inhibit cytochrome, etc. which are summarized in

Table 4 along with references of individual

activities. Recent studies have shown that it is

helpful in enhancing the absorption of Vitamins,



selenium, β-carotene, and promoting body

thermogenic activity naturally 56

. Some

physiochemical studies on pepper starch with

comparison to other starch will give new

application way in near future 81

. Recent research is

more focused to the dynamic use of piperine by

formulating different dosage forms 82, 88, 92, 93

.

Various patent are registered claiming novel use of

piperine 40, 78, 89

. Now it is not only limited to the

activity but also many attempts are made to know

the mechanism, biological pathway for activity

shown by piperine 90, 91

. An individual description

below shows some of the elaborated literature

review of the above potency.

Evidence Based Pharmacological Activities of P.

nigrum and Piperine: Using internet search

engine, accessing to different journals, this attempt

has been made to collect some update research on

P. nigrum or its active constituents (Piperine).

Below Table 4 shows some of the summarized

pharmacological activities of P. nigrum and

piperine.

TABLE 4: PHARMACOLOGICAL ACTIVITIES OF P. NIGRUM

S. no. Activities S. no. Activities

1 Anti-diarrheal 8 15 Effects in metabolism

15, 23, 30

2 Antimicrobial 50,84,85

16 Effect on enzyme 16, 25, 28, 29, 33, 41

3 Antioxidant 9, 38, 93

17 Effects in neurodegeneration and cognitive

impairment 17

4 Anticancer 19

and

tumor reduction activity 43, 44, 45

18 Effect in

Bioavailability 22, 24, 26, 60

5 Antihypertensive 9 19 Toxicity activity

27

6 Anti-asthmatic 20 Effects in stomach 31, 32

7 Anti-inflammatory 20, 40, 86

21 Decrease food transit time 34

8 Anti-obesity 5, 39

, Antidiabetic 87

22 Effect in bile secretion 35

9 Hepatoprotective activity 46

23 Effect in pharmacokinetic of drugs 36, 37

10 Digestive activity 31, 32, 34, 35, 33

24 Synergistic effect with drugs 42

11 Antidepressant 16

25 Inhibition of lungs metastatis 43

12 Immunomodulatory activity 26 Fertility effect 47

13 Analgesic and Antipyretic activity 6 27 Hormonal activity

48

14 Anti-adipogenesis activity 3 28 Anthelmintic activity

75

Taxonomical Classification of Piper nigrum:

Kingdom : Plantae

Subkingdom : Tracheobionta

Superdivision : Spermatophyta

Division : Magnoliophyta

Class : Magnoliopsida

Sub class : Magnoliidae

Order : Piperales

Family : Piperaceae

Genus : Piper

Species : nigrum L.

Antioxidant Activity: Free radicals are responsible

for causing many diseases. Different kinds of free

radicals can attack the cell membrane, and cause or

alter membrane permeability, membrane damage,

oxidation of lipids, loss of different enzymatic

activities, and ultimately disrupt proper cell

function and body physiology, which may cause

cancer. There are many antioxidants in our body to

scavenge the free radical generated normally during

metabolism. However, it can be insufficient

sometimes. When there is imbalance between the

free radical generation and antioxidant activity,

oxidative stress is induced; which is harmful to our

body, causing many side effects from simple health

problems to cancer. Antioxidant activity of our

body system includes enzymes like catalase,

ascorbate, peroxidase, and superoxide dismutase,

which are responsible for scavenging both free

radicals and related oxygen species. Plants are a

potent source of antioxidant activity from

ethnomedicinal practices to today’s finding.

Many scientific findings prove its great antioxidant

potency 38, 56

. Piperine and P. nigrum maintain

superoxide dismutase, glutathione peroxidase,

catalase, glutathione-s-transferase, glutathione

levels and reduce high fat diet induced oxidative

stress 38

. Many screenings, using different solvent

system for extraction of P. nigrum constituents,

prove this potency 77

. The ethanolic extract of P.

nigrum shows high antioxidant potency with 74.61

± 0.02% with IC50 value 14.15 ± 0.02 μg/mg 56

.



The methanolic extract of P. nigrum fruits showing

memory enhancing and antioxidant potency at a

dose of 50 and 100 mg/kg, orally for 21 days in

amloid-β (1-42) were investigated in rat model of

alzheimer's disease 1, 38

. Research in Piper species

viz. P. nigrum, P. guineense and P. umbellatum

shows effects such as protecting cardiac, hepatic,

and renal antioxidant status of atherogenic diet fed

hamster at a dose of 1g/kg and 0.25g/kg for 12

weeks. The significant inhibition of atherogenic

diet induced increased lipid profile and alteration in

antioxidant enzyme activities; showed a great

antioxidant protective role of the piper extract

against atherogenic diet generated oxidative stress

in cardiac, hepatic, and renal tissues 61

. Thus, it will

have important role in scavenging free radicals and

delay aging process. As reported, P. nigrum has

antioxidant potency that may be due to presence of

flavonoids and phenolic contents 1, 77

.

Antimicrobial Activity: An antimicrobial is an

agent that kills micro-organism or inhibits their

further growth. These antimicrobial agents can be

grouped into different categories according to their

primary activity, like antibacterial, antifungal,

antiviral, anti-parasitic, pesticide, etc. Many plants

have been used as an antimicrobial agent

throughout time and will be in future. Although any

modern synthetic antimicrobial agents are

developed rapidly, the resistance towards them is

also growing rapidly. Usually the resistant against

plant source seems less when compared to modern

chemical drugs, this may be due to presence of a

wide variety of different chemical constituent

within a single plant.

Many literature reviews have shown the

antimicrobial potency of black pepper 80

. Extract of

black pepper using solvent viz. carbon

tetrachloride, benzene, ethyl acetate, acetone,

methanol, ethanol, and distilled water were tested

against gram-positive and gram-negative bacteria

viz. Staphylococcus albus, S. typhi, E. coli, B.

megaterium, P. aeruginosa and one fungus,

Pseudomonas aeruginosa 77

. Against different

bacteria, the strongest antibacterial and antifungal

activity was shown at the concentration of

40μg/disc 50

. Using P. nigrum leaf and stem extract,

the silver nanoparticle was synthesized, and the

antibacterial activity was examined against the

agricultural plant pathogen which showed excellent

activity, thus the author concluded its beneficial

application in the field of agricultural

nanotechnology 62

. All 20 strains of K. pneumoniae

were isolated from the urine culture of a

hospitalized patient suffering from urinary tract

infection (UTI) and alcoholic extract of P. nigrum

was tested against it, which showed good activity

against antibiotic resistant Klebsiella pneumonia

with MIC and MBC value at 0.62 mg/ml 51

.

The evaluation of essential oil from P. nigrum for

repellent, developmental inhibitory, and

insecticidal activity against wheat grain pest

Tribolium castaneum showed that the adult of T.

castaneum at 0.2% concentration (v/v) repelled it

significantly. The LD50 for larva and adult was

14.022 μL and 15.262 μL respectively. The

effective concentration (EC50) to decrease the larva

transferred to the pupae to 50% was 6.919 μL 54

. A

protozoal infection, visceral leishmaniasis (VL) is a

life-threatening disease in rural areas and the poor

population in the tropical and sub-tropical

countries. The P. nigrum hexane (PNH) and P.

nigrum ethanolic extract (PNE) of seeds of black

pepper showed profound leishmanicidial activity

against L. donovani promastigoates and

amastigoates via apoptosis 53

.

The antibacterial activity of P. nigrum carried out

against B. subtilis, S. aureus, P. aeruginosa, E. coli,

A. niger, A. alternate, A. flavus and F. oxysporum

showed zone of inhibition from 8-18 mm range.

Maximum for gram positive bacteria S. aureus (18

mm) and minimum against gram negative bacteria

E. coli (8 mm). Similarly, piperine maximum anti-

fungal activity against Fusarium oxysporum (14

mm) and least against A. niger (38 mm) 59

. The

chloroform extract of black pepper showed

significant damage to bacterial cell membrane of E.

coli, and S. aureus followed by disruption of

respiration 83

. All these significant antimicrobial

effects in wide variety of micro-organism signifies

P. nigrum as a powerful natural antimicrobial

agent.

Antidiarrhoeal Effect: Along with above

described antimicrobial activity of black pepper,

against some bacteria77

which are also responsible

for causing diarrhea. Other research signifies its

great potency in controlling diarrhea. As we know,

diarrhea is a leading cause of morbidity and



mortality globally, especially among the children in

developing countries.

Aqueous extract of black pepper at a dose of 75,

150, 300 mg/kg, produces a significant dose-

dependent antimotility, anti-secretory and anti-

diarrheal effects. The author concluded that this

effect is due to the presence of carbohydrates and

alkaloids in black pepper 8.

Analgesic, Antipyretic and Anti-Inflammatory

Activity: In-vivo analgesic activity of piperine was

evaluated in mice. The analgesic activity was tested

by using acetic acid-induced writhing, tail flick

assay. After intraperitoneal (i.p.) injection of

piperine (30, 50 and 70 mg/kg), the acetic acid-

induced writhing in mice was observed and found

to be significantly inhibited (P<0.01), like the

effect of indomethacin- an NSAID drug (20 mg/kg,

i.p.). In the tail flick assay, morphine (5 mg/kg, i.p.)

and piperine (30 and 50 mg/kg, i.p.) showed a

significant increase (P<0.01) in the reaction time of

mice. Animals with naloxone pre-treatment (5

mg/kg i.p.), reversed the analgesic effects of both

morphine and piperine. All these findings reveal

that piperine exhibits analgesic effects possibly

mediated via opioid pathway 63

.

Analgesic activity of piperine was tested in mice

(20 and 30 mg/kg, i.p.); acetic acid and hot plate

reaction test was used. Indomethacin (10 mg/kg)

was taken as reference standard. Piperine showed

significant (p<0.5) dose dependent delayed

response towards pain. The antipyretic activity of

piperine was observed by using yeast-induced

pyrexia in mice model. The rectal temperature was

measured in piperine (20 and 30 mg/kg) treated

mice as compared to the control group. Where the

significant (p<0.5) increase in temperature in the

control group mice was observed 6. The experiment

revealed that anti-inflammatory, analgesic, and

anti-arthritic activity of piperine in arthritis model

of rat. For measuring in-vitro anti-inflammatory

activity, the interleukin 1β stimulated synoviocytes

taken from rheumatoid arthritis was used. While

the anti-arthritic including analgesic potency was

carried out on carrageen, an induced acute paw

model or arthritis and pain in rat. The cyclo-

oxygenase 2, interleukin 6, prostaglandin E2 and

matrix metallo-protease levels were tested by RT-

PCR and ELISA analysis method. At concentration

of 10-100µg/mL, piperine treated group were found

to reduce synthesis of PGE2 in a dose dependent

manner. Even at 10 µg/mL it significantly inhibits

the synthesis of PGE2. The expression of metallo-

proteinase 13 and interleukin 6 were also inhibited 65

. Which concludes the potency of piperine for the

titled topic.

Anticonvulsant Effects: The mice model for

anticonvulsant activity of piperine was evaluated

by inducing seizure with pentylenetetrazol (PTZ)-

and picrotoxin (PIC) in mice. On administering

piperine (30, 50 and 70 mg/kg, i.p.) and reference

standard drugs, valproic acid (200 mg/kg, i.p.),

diazepam (1 mg/kg, i.p.) and carbamazepine (30

mg/kg, i.p.) which showed significantly (P<0.01)

delayed onset of PTZ-and PIC-induced seizures in

mice. Which indicate that piperine exhibits

anticonvulsant effects possibly mediated via

GABA-ergic pathways 63

.

Another experiment on anticonvulsant activity of

piperine in pentylenetetrazol (PTC) and maximal

electroshock (MES) model of convulsion in mice

showed a delay in onset of generalized chronic

seizure and myoclonic jerks with administering

piperine (40- 80 mg/kg) and a significant reduction

of PTZ-induced Fos immune reactivity in dentata

gyrus and MES-induced tonic hind limb extension

after piperine administration. The capsazepine, a

selective TRPV1 antagonist blocked the anti-

seizure effect of piperine 64

. These findings reveal

the potent anti-convulsant activity of piperine.

Antitussive and Bronchodilator: Many traditional

practices prove it as well. P. nigrum is widely used

in many herbal cough syrups due to its potent

antitussive and bronchodilator properties 60

. Many

old people and herbal practitioners believed that the

addition of little amounts of powered peppercorn in

a green tea significantly reduces asthma 4. The oral

administration of piperine in different amount to

mice reduced and suppressed the hyper

responsiveness, infiltration of eosinophils and

inflammation possibly due to suppression of

production of histamine, immunoglobulin E,

interleukin 4 and interleukin 5 66

.

Anti-obesity Activity: Obesity is becoming a

global problem, since it is a socially stigmatized

health problem. The modern treatments are only



effective when they are used, and the problem

progresses again after stopping drug use. On the

other hand, the drugs have more side effects. So,

experiments are now focusing on herbal medicine

and other non-pharmacological way of

management of obesity like exercise, yoga,

meditation, diet control etc.

There are so many plants that have anti-obesity

potency among them, P. nigrum is one. In an anti-

adipogenesis study of P. nigrum extract and

piperine in 3T3-L1 preadipocytes both the black

pepper extract and piperine strongly inhibited the

adipocyte differentiation of 3T3-L1 cells, without

affecting cytotoxicity. The mRNA expression of

masteradipogenic transcription factor, SREBP-1c,

C/EBPβ and PPARγ were significantly decreased.

Piperine disrupts the rosiglitazone- dependent

interaction between PPARγ and cofactor CBP in

GST pull down assay.

Furthermore, in genome-wide analysis using

microarray supports the potent role of piperine in

gene regulation associated with lipid metabolism 3.

In another experiment, supplementing piperine with

high fat diet (40 mg/kg) significantly reduced not

only body weight, total cholesterol, triglyceride,

LDL, VLDL and fat mass but also increased the

level of HDL, with no change in food intake 5.

These results suggest black pepper possesses

potential lipid lowering and fat reducing effects,

without any change in the food appetite.

In another study, black pepper was given to a high-

fat-fed rat in two different doses of 250 mg/kg and

500 mg/kg and piperine at 20 mg/kg was

administered for 10 weeks and the plasma and

tissue lipid profile showed significant reduction in

total cholesterol, phospholipids, free fatty acids,

and triglycerides in both groups. Thus, these all

results suggest that dietary intake of black pepper

or piperine reduces the risk of arthrosclerosis via

hypolipidemic and antiatherogenic effects 58

.

Antimutagenic, Antitumor and Anticancer

Activity: Cancer is becoming global challenge in

today’s health system. Although enormous efforts

are done and going on to find new technology,

drugs, research, surgery, it is still insufficient. So,

we need to search such systems where negligible

side effect with high therapeutic outcomes. Chemo-

therapy is very painful to a patient and has other

serious adverse effects. Many herbal medicines are

used in different systems of medicine, such as

Ayurveda, Chinese, Homeopathy, and so on. Plant

sources are believed having no/negligible side

effects. We should use herbal medicine in our daily

life along with food to avoid cancer and tumors in

our lives. To signify this potency, black pepper has

been used as an anticancer and antitumor agent. P.

nigrum has been reported in many literatures as

having the potency to inhibit tumor formation in

different experimental models 1.

Ethanolic extract of peppercorn and piperine

showed effective immunomodulatory and

antitumor activity 1. As we know, angiogenesis

plays a key role in tumor progression and cancer.

Research findings show that piperine inhibits

proliferation and G1/S transition of human

umbilical vein endothelial cells (HUVECs) without

causing cell death, and also inhibits migration of

HUVEC and in-vitro tubule formation and

angiogenesis induced by collagen and breast cancer

cell in embryo of chick.

Moreover, the phosphorylation is an essential

controller in angiogenesis process and function of

endothelial cells. Interestingly, piperine also

inhibits phosphorylation of Thr 308 residues of Akt

of protein kinas B and Ser 473 too. Thus, piperine

can be a good agent for controlling angiogenesis in

cancer treatment 67

. Prostate cancer is a big

problem for men, causing thousands of deaths a

year. Research has shown that piperine has good

anticancer activity against prostatic cancer cells of

both androgens dependent and independent. A dose

dependent inhibition of the proliferation of 22RV1,

DU-145, PC-3 and LNCaP prostate cancer cells by

piperine was investigated 68

. Piperine from black

pepper modulate lipid peroxidation and activation

of antioxidative protection enzyme, thus reduced

lung cancer 69, 70

.

Anticancer and cancer prevention potency of

piperine free P. nigrum extract (PFPE) against the

N-nitrosomethyllurea (NMU)-induced mammary

tumorigenesis in rat and on breast cancer cells was

carried out and the result showed potent inhibition

in growth of luminal like breast cancer cells via

induction of apoptosis. Moreover, PFPE showed a

higher selectivity against breast cancer cells than



lungs cancer, neuroblastoma cells and colorectal

cancer. In an acute toxicity test, a dose of 5g/kg

single dose for 14 days observation period showed

no mortality and morbidity. The mechanism of

action and cytotoxicity effect in breast cancer cells

was measured by Western blot analysis and MTT

assay respectively 57

. Piperine inhibited growth of

4T1 cells at a dose of 35-280 μmole/L in dose and

time dependent manner with IC50 were 105 ± 1.08

and 78.52 ± 1.06 μmole/L respectively at 48 and

72h. At 70-280 μmole/L dose dependently induced

apoptosis of 4T1 cells via activation of caspase 3.

Piperine injection (5 mg/kg) significantly inhibited

lung metastasis and at injection dose (2.5 and

5mg/kg) cause marked suppression of 4T1 tumor

growth dose-dependently 52

.

Anxiolytic and Antidepressant Activity: In this

globalized world, people are more stressed. Suicide

and mental sub-activity is a big problem in today’s

society. Many herbs are used as a memory

enhancer. Among which, black pepper has been

used for a long time in herbal and ethnomedicinal

practice 22, 76

. Today’s more scientific experimental

model findings prove it is useful. Anxiolytic and

antidepressant activity of the methanolic extract of

P. nigrum fruits in beta-amyloid (1-42) treated rat

model of Alzheimer’s disease showed increase in

immobility and decrease in swimming time within

forced swimming test. Whereas decreases in % of

time spent, exploratory activity and number of

entries in open arm within elevated plus-maze test.

This showed the methanolic extract significantly

exhibited antidepressant and anxiolytic effects by

attenuation of oxidative stress 55

. Another study

was done in corticosteroid induced depression

model of mice. After 3-week corticosterone

injection mice showed depression like behavior

observed by tail suspension test and immobility

time in forced swim test. These depression

behaviors are significantly diminished after

piperine administration 71

. Those finding proves the

potent anxiolytic and antidepressant activity of

black pepper.

Digestive and Hepatoprotective Activity: Many

experimental findings show the hepatoprotective

effect of P. nigrum in animal and human model 4.

The methanolic extract from black pepper (MEPN)

fruits (100 and 200 mg/kg, p.o. for 15 days) and

piperine (50 mg/kg, p.o. for 15 days) were tested

against ethanol-CCl4 induced hepatotoxicity Wistar

rats, which reveals the significant activity of black

pepper in decreasing the hepatic biomarker level

like TG, AST, ALT, ALP and bilirubin, which

were increased on ethanol-CCl4 administration. The

significantly decreased level of SOD, GSH and

CAT after ethanol-CCl4 administration were

restored with MEPN and piperine. These results

were like the reference standard Liv 52 (1ml/kg,

p.o., 15 days) 72

.

Another study where liver toxicity in mice was

induced with D-galactosamine and exposed to dose

dependent piperine, which inhibited increase in

serum GOT and GPT levels and suggested that this

effect dependend on hepatocytes reduced

sensitivity towards tumor necrosis factor-α 73

.

Those study reveals that the P. nigrum possesses

potent hepatoprotective properties which can be

used as therapeutic potential in liver disorder.

The pungent properties of P. nigrum specially the

piperine increases production of the saliva, activate

salivary amylase, and promote gastric secretion,

more over decrease GI transit time 74

. The use of

black pepper as spicy is more. Black pepper

1.5g/meal administration in healthy human

volunteer via intragastrical administration

significantly increases pepsin and parietal

secretion, gastric cell exfoliation and potassium

loss 31

. In rat model administration of piperine 20

mg% for 8 weeks along with fed significantly

enhanced intestinal lipase activity and

disaccharidases the maltase and sucrose, thus

promote digestion 33

.

Other Pharmacological Activities and Use: P.

nigrum (Black pepper) exhibits many

pharmacological actions like antiplatelets, anti-

hypertensive, antispasmodic, antiprotozoal,

bioavailability enhancer 60

, memory enhancer,

antimutagenic, insecticidal, immunomodulator,

antithyroid, anti-asthmatic, anxiolytic activities etc. 1, 47, 52, 55

.

CONCLUSION: Black pepper is a very rich

source of a wide variety of chemical constituents,

most of which are biologically active. The long

practice of using pepper in different traditional

systems of medicine made its scope from the



kitchen, to drugs, to cosmetics. Modern

experimental research on the different biological

activities reveals the significance of its use in

traditional systems of medicine. Many scientific

elaborations about its volatile constituents,

monoterpenes, sesquiterpenes, and specially

piperine have increased the scope in the field of

further activity testing its medicinal and other uses.

Moreover, the synthetic modifications to make a

more potent drug candidate with minimum toxicity

and great significance. New researches are going

on, using different formulation, method of use,

linked with other delivery technology where the

pepper is the main constituent. The pepper’s use in

treating cancer, obesity, hypertension, diabetes,

diarrhea, and its bioavailability signifies its

attraction in the future. Furthermore, specific

research studies are needed to signify the black

pepper is miraculously really the King of species.

ACKNOWLEDGEMENT: Great thanks to

College of Pharmacy, Institute of Pharmaceutical

Research and Development, Wonkwang

University, for providing all services during this

review writing. Special thanks to Mr. Tyler Reimer

for helping in proof checking.

CONFLICT OF INTEREST: The authors have

no conflicts of interest to declare that are directly

relevant to the content of this manuscript.

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How to cite this article:

Joshi DR, Shrestha AC and Adhikari N: A review on diversified use of the King of Spices: Piper nigrum (Black Pepper). Int J Pharm Sci &

Res 2018; 9(10): 4089-01. doi: 10.13040/IJPSR.0975-8232.9(10).4089-01.

joshi et al., ijpsr, 2018; vol. 9(10): 4089-4101. e-issn

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